This project proposes to extend studies on efficacy of an attenuated SHIV vaccine to protect macaques against SHIV/KU-induced AIDS following inoculation of this highly virulent virus on mucosal surfaces. The model is relevant to biological properties of patient isolates of HIV-1. Following a traumatic intravaginal deposition of SHIV/KU into non- immunized sexually mature macaques, the virus caused infection in large cells in the mucosa and within two days, infected cells were present in the pelvic and mesenteric lymph nodes. This was followed by explosive replication in the lymphoid system, resulting in severe global loss of CD4+ T cells within 1 month and AIDS within 8 months in 6/6 macaques. In collaboration with Dr. Harold McClure at Yerkes, we initiated vaccine experiments using attenuated gene-deleted SHIV's in hopes of protecting macaques against SHIV/KU-induced STD. These studies showed that 5/6 macaques injected subcutaneously with deltavpu deltanefSHIV-4 and 6/6 immunized orally with deltavpuSHIV-PPc resisted productive systemic infection and AIDS caused by intravaginally-inoculated SHIV/KU, given 6 months later. In this application, the PI and Dr. McClure plan to further utilize the resources of Yerkes Regional Primate Center to pursue new studies on the vaccine efficacy against SHIV/KU disease using orally inoculated deltavpuSHIV-PPc vaccine. We will collaborate with Dr. J. Sastry at the University of Texas, Bastrop, to study CMI correlates of protection. In five Specific Aims, we will determine 1) whether vaccine protection will last as long as two years; 2) whether vaccination is effective against challenge virus SHIV/KU given orally and rectally in addition to vaginally; 3) whether immunized animals will resist heterologous pathogenic viruses that are not neutralized by antibodies induced by the vaccine virus; 4) whether fetuses become infected during vaccination or challenge of pregnant animals and, 5) whether new born animals exposed to vaccine virus at birth will resist heterologous pathogenic virus later. We will use animals in Aims 1, 2 and 3 to explore immunological correlates of vaccine-induced protection. 70 animals will be used in the five-year period and they will be house at Yerkes.